Composition Containing Sulfoalkyl Ether Cyclodextrin and Latanoprost

ABSTRACT

An aqueous composition of latanoprost and SAE-CD is provided. The composition possesses improved stability over otherwise similar compositions excluding SAE-CD. Methods of and systems for treating diseases, disorders, conditions or symptoms of the eye that are therapeutically responsive to latanoprost are also provided.

FIELD OF THE INVENTION

The present invention relates to compositions comprising sulfoalkylether cyclodextrin and latanoprost and to methods for their preparationand use.

BACKGROUND OF THE INVENTION

Latanoprost ((isopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]-cyclopentyl]hept-5-enoate)is an isopropyl ester analogue of prostaglandin F2α.

The commercially available form of latanoprost (XALATAN®) includes nocyclodextrin and has issues concerning formulation stability.Latanoprost has been demonstrated to undergo substantial UV-B (320 nm to290 nm) catalyzed photolytic degradation even under short exposure time,and it has been demonstrated to undergo substantial thermal and/orhydrolytic degradation at elevated temperatures in a pH dependentmanner. The commercial formulation also contains BAK (benzalkoniumchloride; 0.02%) as preservative; however, BAK has been reported to leadto corneal damage, and such activity is counterproductive to thetherapeutic activity of latanoprost.

Sulfoalkyl ether cyclodextrin (SAE-CD) derivatives are polyanionic,hydrophilic, water soluble cyclodextrins derivatized with sulfoalkylether functional groups. SAE-CD derivatives are commercially availablefrom CyDex Pharmaceuticals, Inc. (Lenexa, Kans.). SAE-CD is currentlymarketed under the trademarks CAPTISOL® and Advasep®.

CAPTISOL® has an average of about 7 sulfoalkyl ether substituents percyclodextrin molecule. The anionic sulfobutyl ether substituentdramatically improves the aqueous solubility and safety of the parentcyclodextrin. Reversible, non-covalent, complexation of drugs withCAPTISOL® generally allows for increased solubility and, in some cases,increased stability of drugs in aqueous solutions.

SUMMARY OF THE INVENTION

The inventors have discovered that latanoprost in solution can bestabilized by SAE-CD under some conditions thereby reducing itsphotolytic and thermal or hydrolytic degradation upon storage insolution and thereby extending the shelf-life of aqueous compositionscontaining the same.

In some embodiments, the invention provides an aqueous compositioncomprising (or consisting essentially of): aqueous carrier; SAE-CD; andlatanoprost, wherein the pH of the composition ranges from 5.5 to 7; themolar ratio of SAE-CD to latanoprost ranges from 2:1 to 40:1; theconcentration of latanoprost ranges from 10 to 500 μg/mL; and theconcentration of SAE-CD ranges from 1 to 100 mg/mL.

The invention also provides a method of treating a diseases, disorder,condition, or symptom that is therapeutically responsive to latanoprost,the method comprising: administering to a subject in need thereof atherapeutically effective amount of latanoprost in an aqueouscomposition according to the invention. In some embodiments, thecomposition is an ophthalmic composition that can be administered to theeye of a subject. In some embodiments, the administering is performedonce or twice daily.

The invention also provides a system for treating, preventing orameliorating a disease, disorder, condition or symptom of the eye in asubject in need thereof comprising: an aqueous composition comprising atherapeutically effective amount of latanoprost,

SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier; and

an administration device for ophthalmic administration of the aqueouscomposition to the subject, wherein the composition is provided in thedevice.

The device for ophthalmic administration can be a dropper, pipette,drop-dispensing package, tube, eye spray device, or eye wash unit. Thedevice can be adapted to emit 1-1000 μL of prostaglandin solution perunit dose. The device can comprise single or plural unit doses.

The device can include a reservoir comprising 0.1-100 mL of the aqueouscomposition, and the device can be adapted for single use or multipleuse. Suitable dispensers are illustratively disclosed in InternationalPatent Publication No. WO 96/06581, the entire disclosure of which ishereby incorporated by reference.

Some embodiments of the invention provide a unit dose of a therapeuticlatanoprost solution comprising: about 1.5 μg of latanoprost per unitdose of solution; SAE-CD; pharmaceutically acceptable aqueous liquidcarrier; and potassium sorbate of about 0.05 to about 0.2% by weight (orabout 0.5% by wt.) of the unit dose, and wherein the solution issuitable for ophthalmic administration to a subject in need thereof.

Some embodiments of the invention also provide a method of treatingpreventing or ameliorating in a subject a latanoprost-responsivedisease, condition, symptom or disorder, the method comprising meteringinto the eye of the subject a therapeutically effective amount oflatanoprost that is about 6 μg or less per day, delivered as 1 or moreunit doses, wherein each unit dose consists essentially of about 1.5 μg(or 1 to 2 μg) of latanoprost; SAE-CD; potassium sorbate of about 0.05to about 0.2% by weight of the unit dose; and a pharmaceuticallyacceptable aqueous liquid carrier.

In some embodiments, the pH ranges from 6 to 7; the molar ratio SAE-CDto latanoprost ranges from 4:1 to 21:1; the concentration of latanoprostranges from 25 to 150 μg/mL; and/or the concentration of SAE-CD rangesfrom 1 to 50 mg/mL.

In some embodiments, the composition further comprises one or moreviscosity modifiers, one or more tonicity modifiers, one or morebuffering agents, one or more preservatives, one or more buffers, or acombination thereof. In some embodiments, the composition excludes BAK(benzalkonium chloride) and/or excludes a preservative. In someembodiments, the composition excludes a viscosity modifier. In someembodiments, the composition is self-preserved. In some embodiments, theformulation is isotonic. In some embodiments, the composition furthercomprises a gelling agent, suspending agent, buffer, preservative or acombination thereof.

In some embodiments, the viscosity of the composition is in the range of1-20,000 cps.

In some embodiments, the aqueous composition is a liquid, suspension,syrup, cream or gel. A suspension can comprise other materials suspendedin the formulation; although, the latanoprost would be dissolved in theformulation.

In some embodiments, a dose of latanoprost comprises a therapeuticallyeffective amount thereof in a volume of composition of 15 to 150 μL.

In some embodiments, SAE-CD comprises a compound, or mixture ofcompounds, of the Formula 1:

wherein:

p is 4, 5 or 6;

R₁ is independently selected at each occurrence from —OH or —SAET;

—SAE is a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, wherein at least one SAE isindependently a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, a —O—(CH₂)_(g)SO₃ ⁻group, wherein g is 2 to 6, or 2 to 4, (e.g. —OCH₂CH₂CH₂SO₃ ⁻ or—OCH₂CH₂CH₂CH₂SO₃ ⁻); and

T is independently selected at each occurrence from the group consistingof pharmaceutically acceptable cations, which group includes, forexample, H⁺, alkali metals (e.g. Li⁺, Na⁺, K⁺), alkaline earth metals(e.g., Ca⁺², Mg⁺²), ammonium ions and amine cations such as the cationsof (C₁-C₆)-alkylamines, piperidine, pyrazine, (C₁-C₆)-alkanolamine,ethylenediamine and (C₄-C₈)-cycloalkanolamine among others; providedthat at least one R₁ is a hydroxyl moiety and at least one R₁ is —SAET.

In some embodiments, the SAE-CD is SAE-α-CD, SAE-β-CD or SAE-γ-CD. TheSAE-CD can be SBE-CD, esp. SBE-β-CD. The average degree of substitutionfor the SAE-CD can range from 1 to 10, 2 to 8, 4 to 8, 6 to 7, or 5 to7.

The invention includes all combinations of the embodiments and aspectsdisclosed herein. Accordingly, the invention includes the embodimentsand aspects specifically disclosed, broadly disclosed, or narrowlydisclosed herein, as well as combinations thereof and subcombinations ofthe individual elements of said embodiments and aspects.

These and other aspects of this invention will be apparent uponreference to the following detailed description, examples, claims, andattached figures.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are given by way of illustration only, and thusare not intended to limit the scope of the present invention.

FIG. 1 depicts a phase solubility diagram for latanoprost in thepresence of SBE-β-CD in an aqueous liquid carrier according to Example5.

FIG. 2 depicts a plot of percentage of latanoprost remaining in solutionversus storage time for aqueous composition containing latanoprost andexposed to UV-B radiation according to Example 6.

FIGS. 3-5 depict plots of percentage of latanoprost remaining insolution versus storage time for aqueous composition containinglatanoprost and varying in pH and concentration of SBE-β-CD according toExample 7.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods of treating ophthalmicdiseases, symptoms, or disorders that are therapeutically responsive tolatanoprost therapy by delivering aqueous compositions comprisinglatanoprost to ophthalmic tissues. The invention is also directed tomethods, systems, devices, and compositions for delivering aqueoussolution composition comprising latanoprost to ophthalmic tissues. Thesystems of the invention comprise an administration device, and acomposition of the invention. The composition of the invention compriseslatanoprost, an aqueous carrier and SAE-CD.

SAE-CD increases the shelf-life of an aqueous formulation comprisingSAE-CD as compared to an aqueous formulation excluding SAE-CD. SAE-CDincreases the stability of latanoprost against photolytic degradation(UV-B) and hydrolytic degradation. SAE-CD increases the aqueoussolubility of latanoprost as compared to an aqueous formulationexcluding SAE-CD.

The SAE-CD included in the composition of the invention is sulfoalkylether cyclodextrin (SAE-CD) derivative (e.g. CAPTISOL® and ADVASEP®),which is an anionic cyclodextrin derivative. The SAE-CD can be acompound or mixture of compounds of the Formula 1.

The terms “alkylene” and “alkyl,” as used herein (e.g., in the—O—(C₂-C₆-alkylene)SO₃ ⁻ group or in the alkylamine cations), includelinear, cyclic, and branched, saturated and unsaturated (i.e.,containing one double bond) divalent alkylene groups and monovalentalkyl groups, respectively. The term “alkanol” in this text likewiseincludes both linear, cyclic and branched, saturated and unsaturatedalkyl components of the alkanol groups, in which the hydroxyl groups maybe situated at any position on the alkyl moiety. The term “cycloalkanol”includes unsubstituted or substituted (e.g., by methyl or ethyl)cyclicalcohols.

When at least one R₁ in the CD molecule is —SAET, the degree ofsubstitution, in terms of the —SAET moiety, is understood to be at leastone. The term SAE is used to denote a sulfoalkyl (alkylsulfonic acid)ether moiety it being understood that the SAE moiety comprises a cation(T) unless otherwise specified. Accordingly, the terms SAE and SAET may,as appropriate, be used interchangeably herein.

Further exemplary SAE-CD derivatives include:

SAEx-α-CD SAEx-β-CD SAEx-γ-CD SEEx-α-CD SEEy-β-CD SEEz-γ-CD SPEx-α-CDSPEy-β-CD SPEz-γ-CD SBEx-α-CD SBEy-β-CD SBEz-γ-CD SPtEx-α-CD SPtEy-β-CDSPtEz-γ-CD SHEx-α-CD SHEy-β-CD SHEz-γ-CDwherein SEE denotes sulfoethyl ether, SPE denotes sulfopropyl ether, SBEdenotes sulfobutyl ether, SPtE denotes sulfopentyl ether, SHE denotessulfohexyl ether, and the values “x”, “y” and “z” represent the averagedegree of substitution as defined herein in terms of the number ofsulfoalkyl ether groups per CD molecule. The salts thereof (with “T” ascation) are understood to be present.

Exemplary SAE-CD derivatives include SBE5.8-α-CD, SBE4-β-CD, SBE6-β-CD,SBE5-β-CD, SBE6.5-β-CD, SBE6.7-β-CD, SBE7-β-CD, SBE11-β-CD, SBE3.4-γ-CD,SBE4.2-γ-CD, SBE4.9-γ-CD, SBE5.2-γ-CD, SBE6.1-γ-CD, SBE7.5-γ-CD,SBE7.8-γ-CD and SBE5-γ-CD which correspond to SAE-CD derivatives herein.

The preparation of SAE-CD derivatives is disclosed in U.S. Pat. No.5,376,645 and No. 5,134,127 to Stella et al. The SAE-CD derivatives orCD derivatives containing a sulfonate functional group can also be madeaccording to Parmerter et al. (U.S. Pat. No. 3,426,011), Gadelle et al.(U.S. Pat. No. 5,578,719), Joullié et al. (U.S. Pat. No. 5,760,015 andNo. 5,846,954), Buchanan et al. (U.S. Pat. No. 6,610,671 and No.6,479,467), Perrier et al. (U.S. Pat. No. 6,524,595), Uchiyama et al.(U.S. Pat. No. 5,512,665), Lammers et al. (Recl. Trav. Chim. Pays-Bas(1972), 91(6), 733-742); Staerke(1971), 23(5), 167-171), Qu et al. (J.Inclusion Phenom. Macro. Chem., (2002), 43, 213-221), Yoshinaga(Japanese Patent No. JP 05001102; U.S. Pat. No. 5,241,059), Zhang et al.(PCT International Publication No. WO 01/40316), Adam et al. (J. Med.Chem. (2002), 45, 1806-1816), and Tarver et al. (Bioorganic & MedicinalChemistry (2002), 10, 1819-1827). SAE-CD can be purchased from CyDexPharmaceuticals, Inc. (Lenexa, Kans.).

The various species of SAE-CD derivative can differ in their degree ofsubstitution by functional groups, the number of carbons in thesulfoalkyl groups, their molecular weight, the number of glucopyranoseunits contained in the base cyclodextrin used to form the derivatizedcyclodextrin and or their substitution patterns. In addition, thederivatization of a cyclodextrin with sulfoalkyl groups occurs in acontrolled, although not exact manner. For this reason, the degree ofsubstitution is actually a number representing the average number offunctional groups per cyclodextrin (for example, SBE7-β-CD, has anaverage of 7 substitutions per cyclodextrin). Thus, it has an averagedegree of substitution (ADS) of about 7. In addition, the regiochemistryof substitution of the hydroxyl groups of the cyclodextrin is variablewith regard to the substitution of specific hydroxyl groups of thehexose ring. For this reason, substitution of the different hydroxylgroups is likely to occur during manufacture of the derivatizedcyclodextrin, and a particular derivatized cyclodextrin will possess apreferential, although not exclusive or specific, substitution pattern.Given the above, the molecular weight of a particular derivatizedcyclodextrin composition may vary from batch to batch.

Within a given SAE-CD derivative composition, the substituents of the CDderivative(s) thereof can be the same. For example, SAE moieties canhave the same type of alkylene (alkyl) radical upon each occurrence in aCD derivative composition. In such an embodiment, the alkylene radicalin the SAE moiety might be ethyl, propyl, butyl, pentyl or hexyl in eachoccurrence in a CD derivative composition.

In a single parent CD molecule, there are 3v+6 hydroxyl moietiesavailable for derivatization. Where v=4 (α-CD), “y” the degree ofsubstitution for the moiety can range in value from 1 to 17. Where v=5(β-CD), “y” the degree of substitution for the moiety can range in valuefrom 1 to 20. Where v=6 (γ-CD), “y” the degree of substitution for themoiety can range in value from 1 to 23. In general, “y” also ranges invalue from 1 to 3v+g, where g ranges in value from 0 to 5. “y” may alsorange from 1 to 2v+g, or from 1 to 1v+g.

The degree of substitution (DS) for a specific moiety (SAE, for example)is a measure of the number of SAE substituents attached to an individualCD molecule, in other words, the moles of substituent per mole of CD.Therefore, each substituent has its own DS for an individual CDderivative species. The average degree of substitution (ADS) for asubstituent is a measure of the total number of substituents present perCD molecule for the distribution of CD derivatives within a CDderivative composition of the invention. Therefore, SAE4.0-CD has an ADS(per CD molecule) of 4.0.

A SAE-CD derivative composition of the invention comprises adistribution of different CD derivative species or molecules. Morespecifically, a SAE-CD derivative composition comprises plural SAE-CDspecies each having a specific individual degree of substitution withregard to the SAE substituent. As a consequence, the average DS (ADS)for SAE of a SAE-CD derivative composition represents an average of theindividual DS (IDS) values of the population of individual molecules inthe composition. For example, a SAE5.2-CD composition comprises adistribution of plural SAEx-CD molecules, wherein x (the DS for SAEgroups) might range from 1 to 10-11 for individual CD molecules;however, the population of SAE-CD molecules is such that the averagevalue for x (the ADS for SAE groups) is 5.2.

Some embodiments of the invention include a SAE-CD derivative wherein aminority of the sulfoalkyl substituent moieties is located at the C-6position, and a majority of the sulfoalkyl substituent moieties islocated at the C-2 and/or C-3 position. Another embodiment of theinvention includes a SAE-CD derivative wherein a majority of thesulfoalkyl substituent moieties is located at the C-6 position, and aminority of the sulfoalkyl substituent moieties is located at the C-2and/or C-3 position. Another embodiment of the invention includes aSAE-CD derivative wherein the sulfoalkyl substituent moieties aresubstantially evenly distributed among the C-2, C-3 and C-6 positions.

The amount and/or concentration of SAE-CD in the composition can bevaried as needed or as described herein to provide a composition thatpossesses a desired physical property, provide therapeutic effectivenessin subjects to which the composition is administered, and/or achieve adesired performance in an administration device. SAE-CD can be presentin an amount sufficient to solubilize and/or stabilize the latanoprost.The aqueous carrier can be present in an amount sufficient to aid indissolution of the latanoprost and form a solution of sufficient volumeand sufficiently low viscosity to permit administration with anadministration device. In some embodiments, SAE-CD is present at aconcentration of about 1 to 150 mg/mL, 1 to 100 mg/mL, 0.5 to 100 mg/mL,1 to 50 mg/mL, 5 to 20 mg/mL, or about 10 to 50 mg/mL or about 1 mg/mL,about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 50mg/mL, about 100 mg/mL or about 150 mg/mL of composition. The SAE-CD canbe present in an amount of 100 μg to 1000 mg per unit dose.

In some embodiments, the aqueous composition is viscous, mucoadhesive,or both viscous and mucoadhesive. The viscosity of the aqueouscomposition can be controlled by varying the concentration of SAE-CD.Higher concentrations of SAE-CD result in increased viscosity, and viceversa, as demonstrated in the table below for CAPTISOL® (SBE7-β-CD).

SBE7-β-CD Density Viscosity % w/w (g/mL) (Cp, 25 C.) 59.4 1.320 527.049.4 1.259 51.9 39.7 1.202 17.0 29.8 1.149 5.91 21.5 3.06 19.7 1.0952.78 10.75 1.84 8.5 1.041 1.75 5.15 1.23 0.0 1.002 1 slope = 0.0053y-intercept = 0.995 correlation = 0.9989

The viscosity of the formulation will generally be less than 1000 cps orin the range of 1-20,000 cps for a liquid composition of the inventionand will generally be less than 100 cps.

Viscosity of the composition can also be controlled by use of aviscosity modifier (viscosity modifying agent). As used herein, a“viscosity modifier” refers to an agent or combination of agents thatcan alter the viscosity of the aqueous composition of the invention. Aviscosity modifier may be used to increase (viscosity enhancer) ordecrease (viscosity-reducing agent) the viscosity of the aqueouscomposition. In general, any liquid suitable for ophthalmicadministration can be used as a viscosity-reducing agent. Exemplaryviscosity-reducing agents include water, aqueous buffer, organicsolvent, surfactant, and combinations thereof. Suitable viscosityenhancers include hydrophilic polymers (water soluble polymers, watergellable polymers, and/or water swellable polymers) as described herein.

In some embodiments, the viscosity modifier is carboxymethylcellulose,which is a viscosity enhancer and promoter of mucoadhesion. Theconcentration of carboxymethylcellulose in the aqueous suspension orsolution of the present invention can be about 0.1% to about 5%, orabout 0.1% to about 2.5% by weight. In some embodiments, thecarboxymethylcellulose is in the form of sodium carboxymethylcellulosesubstituted to a degree that the sodium content of the sodiumcarboxymethylcellulose is about 1% to about 20%.

Since the amount of SAE-CD in the composition can vary, thecorresponding molar ratio of SAE-CD to latanoprost can vary. Increasingthe molar ratio generally results in increased solubilization oflatanoprost. The minimum molar ratio is generally about 2:1 or about4:1. The maximum molar ratio is generally about 40:1 or less, or 30:1 orless or 21:1 or less. In some embodiments, the molar ratio ranges from2:1 to 40:1, 2:1 to 30:1, 2:1 to 21:1, 4:1 to 40:1, 4:1 to 30:1 or 4:1to 21:1.

SAE-CD increases the aqueous solubility of latanoprost. The phasesolubility curve (FIG. 1) for latanoprost in the presence of SBE-β-CD(CAPTISOL®) was obtained according to Example 5. The intrinsicsolubility of latanoprost in water, and in the absence of anysolubilizing agent, is about 40 μg/mL. The invention provides a methodof increasing the solubility of latanoprost in an aqueous composition,the method comprising including SAE-CD and latanoprost in the aqueouscomposition, wherein the molar ratio of SAE-CD to latanoprost, pH,concentration of SAE-CD, and concentration of latanoprost are as definedherein. In some embodiments, the SAE-CD increases the aqueous solubilityof latanoprost by at least 10-fold.

Some embodiments of the invention include those wherein at least 50%wt., at least 75% wt., at least 90% wt., at least 95% wt., at least 98%wt., or all of the latanoprost is dissolved in the composition. As usedin reference to the amount of dissolved latanoprost, a “substantialportion” is at least 20% wt., at least 30% wt., at least 40% wt., or atleast 20% wt. and less than 50% wt. of the latanoprost.

The latanoprost can be present in the composition at a concentration ofabout 1 μg/mL to about 500 μg/mL, about 10 μg/mL to about 500 μg/mL,about 10 μg/mL to about 300 μg/mL, about 20 μg/mL to about 200 μg/mL,about 25 μg/mL to about 150 μg/mL, about 25 μg/mL to about 100 μg/mL,about 25 μg/mL to about 75 μg/mL, or about 50 to 150 μg/mL, or it can bepresent at a concentration of about 10 μg/mL, about 25 μg/mL, about 50μg/mL, about 75 μg/mL, about 100 μg/mL, about 125 μg/mL, about 150μg/mL, about 175 μg/mL, about 200 μg/mL, or about 300 μg/mL, dependingon the volume to be administered.

By “complexed” is meant “being part of a clathrate or inclusion complexwith”, i.e., a complexed therapeutic agent is part of a clathrate orinclusion complex with a cyclodextrin derivative. By “major portion” ismeant greater than about 50% by weight or greater than about 50% on amolar basis. Thus, a formulation according to the present invention maycontain latanoprost wherein more than about 50% by weight is complexedwith SAE-CD. The invention also includes embodiments wherein thelatanoprost is not complexed with the SAE-CD or wherein a minor portionof the latanoprost is complexed with the SAE-CD derivative.

A liquid formulation of the invention may be converted to a solidformulation for reconstitution. A reconstitutable solid compositionaccording to the invention comprises latanoprost, SAE-CD and optionallyat least one other pharmaceutical excipient. This composition can bereconstituted with an aqueous liquid to form a liquid formulationaccording to the invention. The composition can comprise an admixture(minimal to no presence of an inclusion complex) of SAE-CD andlatanoprost-containing solid and optionally at least one solidpharmaceutical excipient, such that a major portion of the latanoprostis not complexed with the SAE-CD prior to reconstitution. Alternatively,the composition can comprise a solid mixture of a SAE-CD andlatanoprost, wherein a major portion of the latanoprost is complexedwith the derivatized cyclodextrin prior to reconstitution. Thereconstitutable solid can also comprise SAE-CD and latanoprost whereinsubstantially all or at least a major portion of the latanoprost iscomplexed with the derivatized cyclodextrin.

The reconstitutable formulation can be prepared according to any of thefollowing processes. A liquid formulation of the invention is firstprepared, then a solid is formed by lyophilization (freeze-drying),spray-drying, spray freeze-drying, antisolvent precipitation, variousprocesses utilizing supercritical or near supercritical fluids, or othermethods known to those of ordinary skill in the art to make a solid forreconstitution.

A liquid vehicle included in a formulation of the invention comprises anaqueous liquid carrier, such as water, aqueous alcohol, or aqueousorganic solvent, or a non-aqueous liquid carrier.

Although not necessary, the formulation of the present invention mayinclude one or more pharmaceutical excipients selected from the groupconsisting of a conventional preservative, antifoaming agent,antioxidant, buffering agent, acidifying agent, alkalizing agent,colorant, complexation-enhancing agent, cryoprotectant, electrolyte,gelling agent, glucose, emulsifying agent, oil, solubility-enhancingagent, stabilizer, tonicity modifier, flavors, sweeteners, complexingagents, fragrances, viscosity modifier, other excipients known by thoseof ordinary skill in the art for use in pharmaceutical formulations, anda combination thereof.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suitableinorganic bases include ammonia, metal oxide and metal hydroxide.Suitable organic amine bases include primary amine, secondary amine,tertiary amine, imidazole, triazole, tetrazole, pyrazole, indole,diethanolamine, triethanolamine, diethylamine, methylamine, tromethamine(TRIS), aromatic amine, unsaturated amine, primary thiol, and secondarythiol. Specific exemplary compounds include ammonia solution, ammoniumcarbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodiumborate, sodium carbonate, sodium bicarbonate, sodium hydroxide,triethanolamine, diethanolamine, alkaline amino acids and trolamine andothers known to those of ordinary skill in the art. A combination ofbases can be used.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium for product stability. Suchcompounds include, by way of example and without limitation, aceticacid, acidic amino acids, citric acid, fumaric acid and other alphahydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid,sulfuric acid, tartaric acid and nitric acid and others known to thoseof ordinary skill in the art.

Inclusion of a conventional preservative in the ophthalmic solutionformulation is optional, since the formulation is self-preserved bySAE-CD depending upon its concentration in solution. Nonetheless, aconventional preservative can be further included in the formulation ifdesired. Preservatives can be used to inhibit microbial growth in thecompositions. The amount of preservative is generally that which isnecessary to prevent microbial growth in the composition for a storageperiod of at least six months. As used herein, a conventionalpreservative is a compound used to at least reduce the rate at whichbioburden increases, but maintains bioburden steady or reduces bioburdenafter contamination. Such compounds include, by way of example andwithout limitation, benzalkonium chloride, benzethonium chloride,benzoic acid, benzyl alcohol, cetyltrimethylammonium bromide,cetylpyridinium chloride, chlorobutanol, chlorocresol,chlorophenoxyethanol, disodium EDTA, imidazolidinyl urea, phenol,phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,phenylmercuric acetate, phenylmercuric borate, phenoxypropanol,thimerosal, metacresol, myristylgamma picolinium chloride, potassiumbenzoate, potassium sorbate, sodium sorbate, sodium benzoate, sodiumpropionate, stabilized chlorine dioxide, sorbic acid, thymol,methylparaben, ethylparaben, propylparaben, butylparaben, salts of anyof the above and others known to those of ordinary skill in the art. Itis understood that some preservatives may interact with the CDderivative thus reducing the preservative effectiveness. Nevertheless,by adjusting the choice of preservative and the concentrations ofpreservative and the CD derivative adequately preserved formulations canbe found.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, acetone, potassium metabisulfite,potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodiumcitrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodiumformaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodiummetabisulfite and others known to those of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, acetic acid, sodium acetate, adipic acid, ammonium chloride,benzoic acid, sodium benzoate, boric acid, sodium bicarbonate, sodiumborate, citric acid, glycine, maleic acid, monobasic sodium phosphate,dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassiummetaphosphate, potassium phosphate, monobasic sodium acetate, sodiumbicarbonate, tris-hydroxymethylaminomethane, sodium tartrate, sodiumcitrate anhydrous and dehydrate, others known to those of ordinary skillin the art, salts of any of the above, and combinations thereof. Otherbuffers include citric acid/phosphate mixture, acetate, barbital,borate, Britton-Robinson, cacodylate, citrate, collidine, formate,maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate,citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)imino-tris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)-butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),TRIZMA™ (tris(hydroxymethylaminomethane), HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine),EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)),TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD(2-amino-2-methyl-1,3-propanediol), and/or any other buffers known tothose of skill in the art. Non-limiting exemplary combinations includecitrate buffer with dextrose, citrate buffer with phosphate buffer.

The pH of the composition can range from about 5.5 to 7.5, about 5.5 to7, or about 6 to 7, or the pH can be about 5.5, about 6, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7 or about 7.5.

A complexation-enhancing agent can be added to a formulation of theinvention. When such an agent is present, the ratio ofcyclodextrin/active agent can be changed. A complexation-enhancing agentis a compound, or compounds, that enhance(s) the complexation of theactive agent with the cyclodextrin. Suitable complexation enhancingagents include one or more pharmacologically inert water solublepolymers, hydroxy acids, and other organic compounds typically used inpreserved formulations to enhance the complexation of a particular agentwith cyclodextrins.

As used herein, the term “gelling agent” is an agent or combination ofagents that cause in situ gellation of the aqueous composition. Agelling agent can be present in an amount (concentration) effective topromote gelling of the aqueous composition upon contact with the eye orwith lacrimal fluid in the exterior of the eye. Suitable gelling agentsinclude, by way of example and without limitation, thermosettingpolymers such as tetra-substituted ethylene diamine block copolymers ofethylene oxide and propylene oxide (e.g., poloxamine 1307);polycarbophil; and polysaccharides such as gellan, carrageenan (e.g.,kappa-carrageenan and iota-carrageenan), chitosan and alginate gums; andcombinations thereof.

Hydrophilic polymers can be used as complexation-enhancing,solubility-enhancing, viscosity enhancer, and/or water activity reducingagents to improve the performance of formulations containing acyclodextrin-based preservative. Loftsson has disclosed a number ofpolymers suitable for combined use with a cyclodextrin (underivatized orderivatized) to enhance the performance and/or properties of thecyclodextrin. Suitable polymers are disclosed in Pharmazie (2001),56(9), 746-747; International Journal of Pharmaceutics (2001), 212(1),29-40; Cyclodextrin: From Basic Research to Market, InternationalCyclodextrin Symposium, 10th, Ann Arbor, Mich., United States, May21-24, 2000 (2000), 10-15 (Wacker Biochem Corp.: Adrian, Mich.); PCTInternational Publication No. WO 9942111; Pharmazie, 53(11), 733-740(1998); Pharm. Technol. Eur., 9(5), 26-34 (1997); J. Pharm. Sci. 85(10),1017-1025 (1996); European Patent Application EP0579435; Proceedings ofthe International Symposium on Cyclodextrins, 9th, Santiago deComostela, Spain, May 31-Jun. 3, 1998 (1999), 261-264 (Editor(s):Labandeira, J. J. Tones; Vila-Jato, J. L. Kluwer Academic Publishers,Dordrecht, Neth); S.T.P. Pharma Sciences (1999), 9(3), 237-242; ACSSymposium Series (1999), 737(Polysaccharide Applications), 24-45;Pharmaceutical Research (1998), 15(11), 1696-1701; Drug Development andIndustrial Pharmacy (1998), 24(4), 365-370; International Journal ofPharmaceutics (1998), 163(1-2), 115-121; Book of Abstracts, 216th ACSNational Meeting, Boston, Aug. 23-27 (1998), CELL-016, American ChemicalSociety; Journal of Controlled Release, (1997), 44/1 (95-99); Pharm.Res. (1997) 14(11), S203; Investigative Ophthalmology & Visual Science,(1996), 37(6), 1199-1203; Proceedings of the International Symposium onControlled Release of Bioactive Materials (1996), 23rd, 453-454; DrugDevelopment and Industrial Pharmacy (1996), 22(5), 401-405; Proceedingsof the International Symposium on Cyclodextrins, 8th, Budapest, Mar.31-Apr. 2, (1996), 373-376. (Editor(s): Szejtli, J.; Szente, L. Kluwer:Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2(6), 277-279;European Journal of Pharmaceutical Sciences, (1996) 4(SUPPL.), S144;Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland,UK Sep. 15-17, 1996; Pharmazie, (1996), 51(1), 39-42; Eur. J. Pharm.Sci. (1996), 4(Suppl.), S143; U.S. Pat. No. 5,472,954 and No. 5,324,718;International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995)126, 73-78; Abstracts of Papers of the American Chemical Society, (2Apr. 1995) 209(1), 33-CELL; European Journal of Pharmaceutical Sciences,(1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11(10),S225; International Journal of Pharmaceutics (Netherlands), (Apr. 11,1994) 104, 181-184; and International Journal of Pharmaceutics (1994),110(2), 169-77, the entire disclosures of which are hereby incorporatedby reference.

Other suitable polymers are well-known excipients commonly used in thefield of pharmaceutical formulations and are included in, for example,Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro(editor), Mack Publishing Company, Easton, Pa., 1990, pp. 291-294;Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy.Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition(Lea & Febinger, Philadelphia, Pa., 1983, pp. 592-638); A. T. Florenceand D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition,MacMillan Press, London, 1988, pp. 281-334. The entire disclosures ofthe references cited herein are hereby incorporated by references. Stillother suitable polymers include water-soluble natural polymers,water-soluble semi-synthetic polymers (such as the water-solublederivatives of cellulose) and water-soluble synthetic polymers. Thenatural polymers include polysaccharides such as inulin, pectin, alginderivatives (e.g. sodium alginate) and agar, and polypeptides such ascasein and gelatin. The semi-synthetic polymers include cellulosederivatives such as methylcellulose, hydroxyethylcellulose,hydroxypropyl cellulose, their mixed ethers such as hydroxypropylmethylcellulose and other mixed ethers such as hydroxyethylethylcellulose and hydroxypropyl ethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts,especially sodium carboxymethylcellulose. The synthetic polymers includepolyoxyethylene derivatives (polyethylene glycols) and polyvinylderivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrenesulfonate) and various copolymers of acrylic acid (e.g. carbomer). Othernatural, semi-synthetic and synthetic polymers not named here which meetthe criteria of water solubility, pharmaceutical acceptability andpharmacological inactivity are likewise considered to be within theambit of the present invention.

The composition of the invention can be present in the form of asuspension, wherein the SAE-CD and latanoprost are dissolved in theaqueous liquid carrier and a particulate ion exchange resin is suspendedin the liquid carrier. In some embodiments, the ion exchange resin is acationic resin.

The cationic resin may provide an additional means of sustained releaseof the latanoprost. Such resins are characterized as either stronglyacidic cation exchange resins, such as those having sulfonic acidfunctionality, or weakly acidic cation exchange resins, such as thosehaving carboxylic acid functionality. The resin is incorporated as afinely divided powder, that is, 95% of the resulting particles (e.g.spheroidal particles) have a diameter less than 20.0 microns. Therelease of the latanoprost by the cation exchange resin and optional ananionic polymer is achieved when ions naturally present in the tearfluid, principally sodium and potassium, compete with the bound basicactive for sites on the polymer vehicle and the ion exchange resin. Thusreleased, the basic active is presented to the eye surface for transportto the receptor sites.

Any pharmaceutical grade cationic ion exchange resin is suitable for theformulation and can be used either in the protonated (hydrogen) form orin the salt (e.g. sodium) form. Such resins are readily available, forexample, from Rohm & Haas under the “Amberlite” tradename and from DowChemical Co. under the “Dowex” tradename.

The ion exchange resin component can be present in the composition at alevel of from 0.05% to 10.0% by weight. The average particle sizediameter of the resin ranges from 1 to 20 microns.

Typically, the average particle size of the commercially available formof the ion exchange material of choice is about 40 to 150 microns. Suchparticles can be conveniently reduced to a particle size in the range ofabout 1.0 to 25 microns by ball milling or according to other knowntechniques of particle size reduction.

As used herein, the term “stabilizer” is intended to mean a compoundused to stabilize the therapeutic agent against physical, chemical, orbiochemical process which would reduce the therapeutic activity of theagent. Suitable stabilizers include, by way of example and withoutlimitation, albumin, sialic acid, creatinine, glycine and other aminoacids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose,glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols,sodium caprylate and sodium saccharin and other known to those ofordinary skill in the art.

One or more pharmaceutically acceptable salts or other solutes can beincluded in the composition in an amount required to bring tonicity ofthe composition into a physiologically acceptable range. As used herein,the term “tonicity modifier” is intended to mean a compound or compoundsthat can be used to adjust the tonicity of the liquid formulation.Exemplary tonicity modifiers include salts having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions. As used herein,the term “tonicity modifier” is intended to mean a compound or compoundsthat can be used to adjust the tonicity of the liquid formulation.Suitable tonicity modifiers include glycerin, lactose, mannitol,dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose andothers known to those of ordinary skill in the art. Other tonicitymodifiers include both inorganic and organic tonicity adjusting agents.Tonicity modifiers include, but are not limited to, ammonium carbonate,ammonium chloride, ammonium lactate, ammonium nitrate, ammoniumphosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate,boric acid, calcium chloride, calcium disodium edetate, calciumgluconate, calcium lactate, citric acid, dextrose, diethanolamine,dimethylsulfoxide, edetate disodium, edetate trisodium monohydrate,fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose,magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol,potassium acetate, potassium chlorate, potassium chloride, potassiumiodide, potassium nitrate, potassium phosphate, potassium sulfate,proplyene glycol, silver nitrate, sodium acetate, sodium bicarbonate,sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide,sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate,sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate,sodium nitrite, sodium phosphate, sodium propionate, sodium succinate,sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate,sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan,uridine and zinc sulfate. In some embodiments, the tonicity of theliquid formulation approximates the tonicity of the tissues of the eye.

An osmotic agent can be used in the compositions to enhance the overallcomfort to the patient upon delivery of the prostaglandin composition.Osmotic agents can be added to adjust the tonicity of SAE-CD containingsolutions. Osmolality is related to concentration of SAE-CD in water. AtSBE7-β-CD concentrations below about 11-13% w/v, the solutions arehypotonic or hypoosmotic with respect to blood and at SBE7-β-CDconcentrations above about 11-13% w/v the SBE7-β-CD containing solutionsare hypertonic or hyperosmotic with respect to blood. Suitable osmoticagents include any low molecular weight water-soluble speciespharmaceutically approved for ophthalmic delivery such as sodiumchloride. The formulation of the invention can also include biologicalsalt(s), potassium chloride, or other electrolyte(s). A tonicitymodifier can be an osmotic agent.

As used herein, the term “antifoaming agent” is intended to mean acompound or compounds that prevents or reduces the amount of foamingthat forms on the surface of the liquid formulation. Suitableantifoaming agents include dimethicone, simethicone, octoxynol andothers known to those of ordinary skill in the art.

As used herein, the term “bulking agent” is intended to mean a compoundused to add bulk to the solid product and/or assist in the control ofthe properties of the formulation during lyophilization. Such compoundsinclude, by way of example and without limitation, dextran, trehalose,sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol,dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and othersknown to those of ordinary skill in the art.

As used herein, the term “cryoprotectant” is intended to mean a compoundused to protect an active therapeutic agent from physical or chemicaldegradation during lyophilization. Such compounds include, by way ofexample and without limitation, dimethyl sulfoxide, glycerol, trehalose,propylene glycol, polyethylene glycol, and others known to those ofordinary skill in the art.

A solubility-enhancing agent can be added to the composition of theinvention. A solubility-enhancing agent is a compound, or compounds,that enhance(s) the solubility of the latanoprost when in a liquidformulation. When such an agent is present, the ratio ofcyclodextrin/latanoprost can be changed. Suitable solubility enhancingagents include one or more cyclodextrins, cyclodextrin derivatives,SAE-CD, organic solvents, detergents, soaps, surfactant and otherorganic compounds typically used in parenteral formulations to enhancethe solubility of a particular agent. Exemplary solubility enhancers aredisclosed in U.S. Pat. No. 6,451,339; however, other surfactants used inthe pharmaceutical industry can be used in the formulation of theinvention. Some suitable cyclodextrin include underivatizedcyclodextrins and cyclodextrin derivatives, such as SAE-CD, SAE-CDderivatives, hydroxyalkyl ether cyclodextrin and derivatives, alkylether cyclodextrin and derivatives, sulfated cyclodextrin andderivatives, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD,methyl-β-cyclodextrin, carboxyalkyl thioether derivatives, succinylcyclodextrin and derivatives, and other cyclodextrin suitable forpharmaceutical use. SAE-CD cyclodextrins are particularly advantageous.

Suitable organic solvents that can be used include, for example,ethanol, glycerin, poly(ethylene glycol), propylene glycol, poloxamer,aqueous forms thereof and others known to those of ordinary skill in theart.

It should be understood, that compounds used in the art ofpharmaceutical formulations generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

A composition according to the invention can have its oxygen removed.For example, the headspace of the container with the liquid formulationis made oxygen free, substantially oxygen free, or oxygen-reduced bypurging the headspace with an inert gas, such as nitrogen or argon, orby bubbling the inert gas through the liquid formulation. In this way, asubstantial portion of the oxygen dissolved in, and/or in surfacecontact with the solution is removed. For long-term storage, the liquidformulation containing an active agent subject to oxidative degradationcan be stored in an oxygen-free or oxygen-reduced environment. Removalof oxygen from the formulation will enhance preservation of theformulation against aerobic microbes; whereas, addition of oxygen to theformulation will enhance preservation against anaerobic microbes.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “patient” or “subject” are taken to mean warmblooded animals such as mammals, for example, cats, dogs, mice, guineapigs, horses, bovine cows, sheep, non-humans, and humans.

A composition of the invention will comprise an active agent present inan effective amount. By the term “effective amount”, is meant the amountor quantity of active agent that is sufficient to elicit the required ordesired response, or in other words, the amount that is sufficient toelicit an appreciable biological response when administered to asubject.

A liquid composition of the invention can be prepared as follows. Afirst method comprises the steps of: forming a first aqueous solutioncomprising a cyclodextrin derivative; forming a second solution orsuspension comprising active agent; and mixing the first and secondsolutions to form the liquid formulation. A second method is similar tothe first step except that the active agent is added directly to thefirst solution without formation of the second solution. A third methodis similar to the first except that the cyclodextrin derivative is addeddirectly to the second solution/suspension without formation of thefirst solution. A fourth method comprises the steps of: adding asolution/suspension comprising active agent to a powdered or particulatecyclodextrin derivative. A fifth method comprises the steps of: addingthe active agent directly to the powdered or particulate cyclodextrinderivative; and adding a second solution. A sixth method comprises thesteps of: creating the liquid formulation by any of the above methodsand then isolating a solid material by lyophilization, spray-drying,spray-freeze-drying, antisolvent precipitation, a process utilizing asupercritical or near supercritical fluid, or other methods known tothose of ordinary skill in the art to make a powder for reconstitution.

A composition of the invention can be sterilized by: 1) filtrationthrough a filtration medium having a pore size of 0.1 microns or larger;2) irradiation; and/or 3) autoclaving.

A dose of an ophthalmic formulation comprising the aqueous compositionof the invention can be administered to the eye of a subject in needthereof.

The volume or amount of composition administered can vary according tothe intended delivery target and administration device used. The amountof latanoprost in a dose or unit dose can vary according to the intendeddelivery target and administration device used.

The compositions can be administered via an administration devicesuitable for ophthalmic administration of pharmaceutical compositions.As used herein, an administration device is any pharmaceuticallyacceptable device adapted to deliver a composition of the invention to asubject's eye(s). An ophthalmic administration device can be a dropper,pipette, drop dispensing package, tube, eye spray device, eye wash unit,and other devices known to those of ordinary skill in the art.

An administration device can comprise a reservoir containing the aqueouscomposition of the invention. The amount of aqueous composition may varyaccording to the reservoir capacity. An administration device cancomprise one or more unit doses. In general, the total volume of aqueouscomposition in an administration device comprises at least the volume ofa single unit dose up to the volume of generally 60 to 240 unit doses. Adevice that comprises more than one unit dose is referred to as amulti-dose device. The volume of aqueous composition in a multi-dosedevice typically ranges from 100 μl to 10 mL, 200 μl to 5 ml, or 300 μlto 2.5 mL.

The fill volume for the reservoir of a multi-dose administration devicemust be sufficient to provide for the number of actuations required toprovide the desired number of doses in a consistent manor. The reservoirof an administration device can comprise an overfill. As used herein,“overfill” is the amount or percentage of extra composition (either interms of the volume or weight of the composition or the amount of drugin the composition) added to the composition in the reservoir tocompensate for the tail-off characteristics of the device. In someembodiments, the overfill is at least about 1%, at least about 2.5%, atleast about 5%, at least about 7.5%, at least about 10%, at least about15%, at least about 25%, at least about 35%, at least about 45%, atleast about 50% of the target volume or weight of composition in a unitdose or dose of the composition.

Packaging and containers suitable for use as multi-dose devices include,by way of example and without limitation, a bottle, vial, pipette,ampoule, syringe, blister, capsule or other devices. The packaging canbe in a preservative free system such as blow/fill/seal droppercontainer or form/fill/seal dropper container.

The administration device can employ single use (single dose) ormulti-use (multi-dose) packaging. An administration device can be usedrepeatedly with single use or multi-use packages and/or containers.

As used herein, a dose includes a unit dose, dose to subject, dose toeye, or other such term of art. Unless otherwise specified, the term a“unit dose” is a single dose, such as a single drop from anadministration device. An administration of an effective amount,effective dose, or therapeutically effective amount to a subject cancomprise one or more unit doses. In certain embodiments, the effectivedose can be a single unit dose administered to one eye. In certainembodiments, the therapeutically effective amount can be two unit dosesadministered to one eye. In certain embodiments, the effective dose canbe two unit doses, with one unit dose administered to each eye. In someembodiments, the therapeutically effective amount can be more than twounit doses, with more than one dose administered to an eye. The term“effective amount” or “effective dose” or “therapeutically effectiveamount” is the amount or quantity of active agent that is sufficient toelicit the required or desired therapeutic effect, or the amount that issufficient to elicit an appreciable biological response whenadministered to a subject when given at one event or period ofadministration. A single period of administration can compriseadministration of 1, 2 or more unit doses. For administration with ametered administration device, i.e., a device that provides a fixedvolume or amount of composition upon actuation, e.g., pump, squeezebottle, dropper, and other similar devices, the event of administration,for delivery of an effective dose, is a predetermined number ofactuations of the device which releases a corresponding predeterminednumber of unit doses, e.g., 1 to 4 actuations of the administrationdevice releases 1 to 4 unit doses in one or both eyes of a subject. Theunit dose of latanoprost delivered is assumed to be the amount oflatanoprost emitted from the administration device, i.e., the emitteddose.

The daily dose of latanoprost is generally about 0.75 μg to about 6 μg,about 0.75 μg to about 4.5 μg, about 0.75 μg to about 3 μg, or about0.75 μg, or about 1.5 μg, depending on the disease, disorder, conditionor symptom being treated, in accordance with the 2007 Physician's DeskReference (PDR). The dose required to achieve a desired clinicalendpoint, clinical benefit or therapeutic benefit can be lower than thecorresponding dose indicated in the PDR.

An appropriate dosage, frequency and duration of administration, i.e.,treatment regimen, to be used in any particular situation will bereadily determined by one of skill in the art without undueexperimentation, and will depend, among other factors, on the particulardisease, disorder, symptom or condition to be treated or prevented, onthe age, weight and general physical condition of the subject, and onother medication being administered to the subject. Response totreatment according to the present method be monitored and the treatmentregimen be adjusted if necessary in light of such monitoring.

The ophthalmic composition of the invention can be prescribed andadministered to a subject as needed to provide the desired level ofclinical benefit. A desired dosage of latanoprost can be metered byadministration of a known number of drops into the eye. For example, fora drop volume of 25 μL, administration of 1-6 drops will deliver 25-150μL of the composition. In general, a subject can be administered 1 to 4drops per eye at a dosing frequency of 1 to 4 times per day. In someembodiments, a subject is administered 1 to 2 drops per eye at a dosingfrequency of 1 to 2 times per day, or 1 drop per eye per day of anaqueous composition as described herein. It should be noted that thetypical volume of a drop from an eye dropper ranges from about 15 toabout 100 μL, about 20 to about 80 μL, about 25 to about 50 μL, or about30 to about 40 μL.

The composition can be administered at any time of day or night. In someembodiments, the composition is administered to a subject in the eveningor within an hour prior to the time the subject goes to sleep. In someembodiments, the composition is administered in the daytime and/or thenighttime.

A dose of latanoprost can also be administered once daily, every otherday, once every two days, seven days per week, once every week, onceevery month, for an extended period of time, such as several days,weeks, or even longer, or even less frequently.

Some embodiments of the invention include those wherein a unit dose ofaqueous composition comprises about 1 to about 2 μg or about 1.5 μg in avolume of composition of about 25 to about 50 μL or about 30 to about 40μL, wherein the unit dose is administered to a subject in need thereofonce or twice daily per eye.

In terms of the phrase “per eye”, it should be understood that an eyesuffering from a latanoprost-responsive disease, disorder, condition orsymptom is being referred to. Accordingly, a composition of theinvention can be administered to one or both eyes of subject in needthereof, since one or both eyes, respectively, might be in need oftreatment.

The composition of the invention can be administered to a subject inneed thereof for the treatment of one or more disorders, diseases,conditions, or symptoms that are therapeutically responsive tolatanoprost, e.g. one or more latanoprost-responsive disorders,diseases, conditions, or symptoms. A latanoprost-responsive disease,condition, symptom or disorder is one wherein a subject suffering fromsuch will receive a clinical benefit after administration of alatanoprost-containing composition according to the invention. Exemplarydisorders, diseases or symptoms include glaucoma, open-angle glaucoma,elevated intraocular pressure, and ocular hypertension.

A composition of the invention possesses enhanced stability oflatanoprost against UV-B catalyzed photolytic degradation thereof ascompared to the commercial XALATAN® formulation or as compared to anaqueous liquid formulation excluding SAE-CD. FIG. 2 depicts a plot ofdata obtained from a study of the stability of latanoprost(concentration of latanoprost remaining versus period of storage)conducted according to Example 6. The invention provides a method ofincreasing the stability of latanoprost in an aqueous compositionagainst photolytic degradation catalyzed by UV-B radiation, the methodcomprising including SAE-CD in the composition in an amount sufficientto suppress or reduce the rate or extent of photolytic degradation oflatanoprost when exposed to UV-B radiation as compared to the rate orextent of photolytic degradation observed in an otherwise similaraqueous composition excluding SAE-CD and exposed to the same conditions.

The composition also possesses enhanced stability against hydrolyticdegradation of latanoprost in aqueous solution as compared to thecommercial XALATAN® formulation or as compared to an aqueous liquidformulation excluding SAE-CD. FIGS. 2-4 depict plot of data obtainedfrom studies (Example 7) of the stability of latanoprost to solutions ofdifferent pH. The invention provides a method of increasing thestability of latanoprost in an aqueous composition against hydrolyticdegradation, the method comprising including SAE-CD in the compositionin an amount sufficient to suppress or reduce the rate or extent ofhydrolytic degradation of latanoprost as compared to the rate or extentof hydrolytic degradation observed in an otherwise similar aqueouscomposition excluding SAE-CD and exposed to the same conditions.

The compositions of the invention can generally have a storage shelflife of at least 3 mo at 60° C., or at least one year at room temp or atleast two years at room temperature. In this case, shelf life isdetermined only as regards the increase in the amount of latanoprostdegradation by-products or a reduction in the amount of latanoprostremaining in the composition. For example, for a composition having ashelf life of at least six months, the composition will not demonstratean unacceptable and substantial increase in the amount of degradantsduring the storage period of at least six months. The criteria foracceptable shelf-life are set as needed according to a given product andits storage stability requirements. In other words, the amount ofdegradants in a composition having an acceptable shelf-life will notincrease beyond a predetermined value during the intended period ofstorage. On the other hand, the amount of degradants of a compositionhaving an unacceptable shelf-life will increase beyond the predeterminedvalue during the intended period of storage.

In view of the above description and the examples below, one of ordinaryskill in the art will be able to practice the invention as claimedwithout undue experimentation. The foregoing will be better understoodwith reference to the following examples that detail certain proceduresfor the preparation of molecules, compositions and formulationsaccording to the present invention. All references made to theseexamples are for the purposes of illustration. The following examplesshould not be considered exhaustive, but merely illustrative of only afew of the many embodiments contemplated by the present invention.

Example 1 Preparation of an Aqueous Liquid Composition of SAE-CD andLatanoprost

SAE-CD is added to an aqueous liquid carrier to form a solution ofSAE-CD. Latanoprost is added to the solution of SAE-CD with mixing toform the aqueous liquid composition of the invention. Excipients areoptionally included in the formulation. The pH of the composition is inthe range of 6 to 7. The molar ratio of SAE-CD to latanoprost is in therange of 2:1 to 40:1 or 4:1 to 21:1. The concentration of latanoprost inthe final composition is in the range of 10 to 300 μg/mL, 25 to 150μg/mL, 25 to 100 μg/mL, 25 to 75 μg/mL, or 50 to 150 μg/mL, or about 10μg/mL, about 25 μg/mL, about 50 μg/mL, about 75 μg/mL, about 100 μg/mL,about 150 μg/mL or about 300 μg/mL. The concentration of SAE-CD is inthe range of 0.5 to 100 mg/mL, 1 to 50 mg/mL, 5 to 20 mg/mL, or about 10to 50 mg/mL of about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15mg/mL, or about 20 mg/mL.

Example 2 Preparation of an Aqueous Liquid Composition of SBE-β-CD andLatanoprost

Preservative-free aqueous liquid compositions can be made according toExample 1 or as follows.

A buffered isotonic solution is prepared at pH 6.7 using 50 mM phosphatebuffer solution (sodium dihydrogen phosphate monohydrate, disodiumhydrogen phosphate anhydrous and sodium chloride) containing 10 mg/mLSBE-β-CD. To 100 ml of this solution is added 5 mg latanoprost withstirring until the latanoprost is completely dissolved. The resultingsolution contains approximately 0.05 mg/mL latanoprost. The solution isfiltered and sterilized using 0.2 μm PVDF filter, and 0.4 ml of filteredsolution is filled into each of sterile single-use eye-droppercontainers, such as form-fill-seal LDPE.

Ingredient Comp. 2a Comp. 2b Comp. 2c Comp. 2d SBE7-β-CD 10 5 1 15(mg/mL) (1% w/v) (0.5% w/v) (0.1% w/) (1.5% w/v) Latanoprost 50 100 50150 (μg/mL (0.005% (0.01% w/v) (0.005% (0.015% w/v) w/v) w/v) MolarRatio 40:1 10:1 4:1 20:1 (SAE-CD to Latanoprost) Water 100 100 100 100(mL) Buffer 50 10 50 None - (mM) (NaH₂PO₄ + (Citric Acid + (NaH₂PO₄ +adjust Na₂HPO₄) Sodium Na₂HPO₄) with Citrate) NaOH and HCl pH 6.7 6 75.5

Example 3 Preparation of an Aqueous Liquid Composition of SBE-γ-CD andLatanoprost

Viscosity-enhanced aqueous liquid compositions can be made according toExample 1 or as follows.

A buffered isotonic solution is prepared at pH 6.7 using 50 mM phosphatebuffer solution (sodium dihydrogen phosphate monohydrate, disodiumhydrogen phosphate anhydrous and sodium chloride) containing 10 mg/mLSBE-gamma-CD and 17% poloxamer 407 (apolyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer,supplied as Pluronic™ F-127 of BASF). To 100 ml of this solution isadded 5 mg latanoprost with stirring until the latanoprost is completelydissolved. The resulting solution contains approximately 0.05 mg/mLlatanoprost. The solution is filtered and sterilized using 0.2 μm PVDFfilter, and 2.5 ml of filtered solution is filled into each of 5 mLclear low density polyethylene bottle with a clear low densitypolyethylene dropper tip, a high density polyethylene screw cap and atamper-evident overcap.

Ingredient Comp. 3a Comp. 3b Comp. 3c Comp. 3d SBE4.2-γ- 5 5 1 15 CD(0.5% w/v) (0.5% w/v) (0.1% w/) (1.5% w/v) (mg/mL) Latanoprost 50 100 50150 (μg/mL (0.005% w/v) (0.01% w/v) (0.005% (0.015% w/v) w/v) MolarRatio 22:1 11:1 4:1 22:1 (SAE-CD to Latanoprost) Viscosity Poloxamer-407Poly- Glycerin 3% Poly- modifier 17% propylene ethylene (% w/v) glycol15% glycol 10% Water 100 100 100 100 (mL) Buffer 50 50 50 50 (mM)(NaH₂PO₄ + (NaH₂PO₄ + (NaH₂PO₄ + (NaH₂PO₄ + Na₂HPO₄) Na₂HPO₄) Na₂HPO₄)Na₂HPO₄) pH 6.7 6.7 6.7 6.7

Example 4 Preparation of an Aqueous Liquid Ophthalmic Composition ofSBE-β-CD and Latanoprost

Aqueous liquid compositions with added preservative can be madeaccording to Example 1 or as follows.

A buffered isotonic solution is prepared at pH 6.7 using 50 mM phosphatebuffer solution (sodium dihydrogen phosphate monohydrate, disodiumhydrogen phosphate anhydrous and sodium chloride) containing 10 mg/mLSBE-beta-CD and potassium sorbate 0.2%. To 100 ml of this solution isadded 5 mg latanoprost with stirring until the latanoprost is completelydissolved. The resulting solution contains approximately 0.05 mg/mLlatanoprost. The solution is filtered and sterilized using 0.2 μm PVDFfilter, and 2.5 ml of filtered solution is filled into each of 5 mLclear low density polyethylene bottle with a clear low densitypolyethylene dropper tip, a high density polyethylene screw cap and atamper-evident overcap.

Ingredient Comp. 4a Comp. 4b Comp. 4c Comp. 4d SBE7-β-CD 10 5 1 15(mg/mL) (1% w/v) (0.5% w/v) (0.1% w/) (1.5% w/v) Latanoprost 50 100 50150 (μg/mL (0.005% w/v) (0.01% w/v) (0.005% (0.015% w/v) w/v)Preservative Potassium Methyl- Sorbic acid Phenyl- (mg/mL) sorbateparaben 0.2% mercuric 2 (0.2% w/v) 0.05% nitrite 0.002% Molar Ratio 40:110:1 4:1 20:1 (SAE-CD to Latanoprost) Water 100 100 100 100 (mL) Buffer50 50 50 50 (mM) (NaH₂PO₄ + (NaH₂PO₄ + Na₂HPO₄) (NaH₂PO₄ + Na₂HPO₄)Na₂HPO₄) (NaH₂PO₄ + Na₂HPO₄) pH 6.7 6.7 6.7 6.7

Example 5 Determination of Phase Solubility Curve of Latanoprost in thePresence of SAE-CD

Aqueous compositions containing latanoprost and different amounts ofSBE-13-CD were prepared. Latanoprost (1 mg was measured into aluminumweighing boats (size 4×12×4 mm) by using a microbalance. The boats wereput into the amber glass vials (Kimble vial, 1 dram) with Teflon-linedscrew caps. Using a Rainin pipetman, 2.0 mL of SBE-β-CD test solution(0, 5, 10, or 20% w/v) were added to each vial. Each vial was capped,vortexed, placed on a rocker platform and gently mixed at roomtemperature. After 24 hours, the test vials were removed from the rockerplatform, the solutions were centrifuged at 2500 rpm for 5 min, and thesupernatants were filtered through 0.22 micron Millipore PVDF Millex-GVfilters and the pH measured. The latanoprost in the aliquots was assayedby HPLC.

Latanoprost (mg/mL) pH without CAPTISOL ® 40.0 8.57 with 5% w/vCAPTISOL ® >500 7.41 with 10% w/v CAPTISOL ® >500 6.93

In solutions containing at least 5% w/v of SAE-CD, the solubility oflatanoprost exceeded 500 μg/mL.

Example 6 Determination of Photolytic Stability of Aqueous Compositionsof Latanoprost

Latanoprost was measured in weighing boats (size 4×12×4 mm) by using amicrobalance. The boats were put into 50 mL volumetric flask and 100 mMisotonic phosphate buffer (pH 6.7) was added to the flask. The flask wasshaken, sonicated and vortexed over an hour. The solution was filteredthrough a PVDF filter with 20 mL of plastic syringe. SBE-β-CD 0, 1, 5%w/v and BAK 0.02% w/v were measured into each 10 mL volumetric flask andthe filtered latanoprost solution were added to them. The flasks wereshaken for a few minutes at R.T, and then these solutions and XALATAN®were put into quartz vessels. The Rayonet photochemical chamber reactorwas used for the irradiation with RMR-3000A lamp. At various timepoints, the latanoprost in the aliquots was assayed by HPLC, and thesolution pH's were measured before and after the light irradiation.

SAE-CD concentrations of 1% or 5% w/v were sufficient to suppressphotolytic degradation of latanoprost as compared to a solutionexcluding SAE-CD.

Latanoprost HPLC Conditions:

Instrument: Perkin-Elmer Series 200 Autosampler, Pump, and Diode ArrayDetector Column: Supelco Discovery RP Amide C16 4.6 × 250 mm 5 μm MobilePhase: Phosphate acid aqueous pH 3:Acetonitrile (50:50) Wavelength λ =214 nm Flow Rate: 1.0 mL/min Injection 20 μL Volume

Example 7 Determination of Hydrolytic Stability of Aqueous Compositionsof Latanoprost

Latanoprost was measured in weighting boats (size 4×12×4 mm) by using amicrobalance. The boats were put into 50 mL volumetric flask and 10 mMor 100 mM isotonic phosphate buffer (pH 5.5, 6.7 and 8.0) was added tothe flask. The flask was shaken, sonicated and vortexed over an hour.The solution was filtered through a PVDF filter with 20 mL of plasticsyringe. SBE-β-CyD 0, 1, 2.5, 5% w/v or BAK 0.02% were measured into6-dram amber vials, and the filtered latanoprost solution (12 mL) wasadded to each vials. The vials were shaken for a few minutes at R.T, andthen there were kept at 60° C. At various time points, the latanoprostin the aliquots was assayed by HPLC and the solution pH's were measured.

SAE-CD concentrations of 1% or 5% w/v were sufficient to suppresshydrolytic degradation of latanoprost at pH 5.5 and 6.7 (60° C.) ascompared to a solution excluding SAE-CD. SAE-CD was also able tosubstantially reduce hydrolytic degradation of latanoprost at pH 8 (60°C.) as compared to a solution excluding SAE-CD.

Example 8 Measuring Viscosity of Aqueous Solutions Containing SAE-CDUsing a Cone and Plate Viscometer

A Brookfield Programmable DV-III+ Rheometer, CPE-40 cone and CPE 40Yplate (Brookfield Engineering Laboratories, Middleboro, Mass.) is usedto make measurements on 0.5 ml samples at 1, 2, 3, 5 and 10 rpm. Samplesare sheered for approximately 5 revolutions prior to each measurement.This allows for accurate rheological characterization of the samples.The temperature of all samples is equilibrated to 25+/−1 degreecentigrade using a double wall viscometer cone supplied with water froman electronically controlled thermostatic circulating water bath (Model,8001, Fisher Scientific, Pittsburgh, Pa.). The viscometer is calibratedusing 5 and 50 centipoise using silicon oil calibration standards.Viscosity measurements are made at 5 or more rotation speeds to look forsheer thinning behavior (viscosities that decrease as the rate of sheerincreases). Higher rotation speeds result in increased rates of sheer.

Example 9 Preparation of a Stabilized Aqueous Liquid OphthalmicComposition of SBE-β-CD and Latanoprost

Aqueous liquid compositions with added stabilizer can be made accordingto Example 1 or as follows.

A buffered isotonic solution is prepared at pH 6.7 using 50 mM phosphatebuffer solution (sodium dihydrogen phosphate monohydrate, disodiumhydrogen phosphate anhydrous and sodium chloride) containing 10 mg/mLSBE-beta-CD and disodium EDTA dehydrate 0.04%. To 100 ml of thissolution is added 5 mg latanoprost with stirring until the latanoprostis completely dissolved. The resulting solution contains approximately0.05 mg/mL latanoprost. The solution is filtered and sterilized using0.2 μm PVDF filter, and 2.5 ml of filtered solution is filled into eachof 5 mL clear low density polyethylene bottle with a clear low densitypolyethylene dropper tip, a high density polyethylene screw cap and atamper-evident overcap.

Ingredient Comp. 11a Comp. 11b Comp. 11c SBE7-β-CD 10 10 10 (mg/mL) (1%w/v) (1% w/v) (1% w/v) Latanoprost 50 50 50 (μg/mL (0.005% w/v) (0.005%w/v) (0.005% w/v) Stabilizer Na₂-EDTA Sodium Sodium sulfate (mg/mL)dehydrate bisulfate 0.1% 0.2% (0.04% w/v) Molar Ratio 40:1 40:1 40:1(SAE-CD to LATAN) Water 100 100 100 (mL) Buffer 50 50 50 (mM) (NaH₂PO₄ +(NaH₂PO₄ + (NaH₂PO₄ + Na₂HPO₄) Na₂HPO₄) Na₂HPO₄) pH 6.7 6.7 6.7

Example 10 Preparation of an Aqueous Liquid Ophthalmic Composition ofSBE-β-CD and Latanoprost

Aqueous liquid compositions with added gelling agent and stabilizer canbe made according to Example 1 or as follows.

A buffered isotonic solution is prepared at pH 6.7 using 50 mM phosphatebuffer solution (sodium dihydrogen phosphate monohydrate, disodiumhydrogen phosphate anhydrous and sodium chloride) containing 10 mg/mLSBE-beta-CD and disodium EDTA dehydrate 0.04%, iota-carrageenan 0.5%,iota-carrageenan with calcium 0.3% and glycerin 1.5%. To 100 ml of thissolution is added 5 mg latanoprost with stirring until the latanoprostis completely dissolved. The resulting solution contains approximately0.05 mg/mL latanoprost. The solution is filtered using 0.2 μm PVDFfilter, and 2.5 ml of filtered solution is filled into each of 5 mLclear low density polyethylene bottle with a clear low densitypolyethylene dropper tip, a high density polyethylene screw cap and atamper-evident overcap.

Ingredient Comp. 12 SBE7-β-CD 10 (1% w/v) (mg/mL) Latanoprost 50 (0.005%w/v) (μg/mL Stabilizer Na₂-EDTA dehydrate (% w/v) 0.04% Gelling agentIota-carrageenan (mg/mL) (0.5% w/v) Gelling agent Iota-carrageena +Calcium (mg/mL) (0.3%) Viscosity glycerin modifier (1.5% w/v) (% w/v)Molar Ratio 40:1 (SAE-CD to LATAN) Water 100 (mL) Buffer 50 (NaH₂PO₄ +Na₂HPO₄) (mM) pH 6.7

Example 11 Preparation of a Preserved Aqueous Suspension OphthalmicComposition of SBE-β-CD and Latanoprost

Aqueous suspension compositions with added preservative can be madeaccording to Example 1 or as follows.

Finely divided Amberlite IRP-69 resin, a sodium poly(styrene-divinylbenzene) sulfonate, and latanoprost are mixed in 50% of the total watervolume component to form a uniform dispersion. The Carbopol-934P(suspending agent) is added slowly as an aqueous dispersion. The mixtureis homogenized at high speed. The other ingredients, 10 mg/mLSBE-beta-CD and potassium sorbate (preservative) are added as aqueoussolutions. The final volume is made on addition of water. The resultantproducts are white uniform suspensions.

Example 12 Preparation of an In Situ Gelling Preserved AqueousOphthalmic Composition of SBE-β-CD and Latanoprost

An in situ-gelling aqueous suspension compositions with addedpreservative can be made according to Example 1 or as follows.

Gelrite is a purified anionic heteropolysaccharide derived from gellangum. Latanoprost is dissolved in water containing 10 mg/mL SBE-beta-CD,1% Gelrite gellan gum (gelling agent) and 0.2% potassium sorbate(preservative).

The entire disclosures of the references cited herein are herebyincorporated in their entirety. The term about is taken to mean+/− 10%of a corresponding or indicated value.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims. All of the embodiments disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure.

1. An aqueous composition comprising: aqueous carrier; SAE-CD; andlatanoprost, wherein the pH of the composition ranges from 5.5 to 7; themolar ratio of SAE-CD to latanoprost ranges from 2:1 to 40:1; theconcentration of latanoprost ranges from 10 to 500 μg/mL; and theconcentration of SAE-CD ranges from 1 to 100 mg/mL.
 2. A unit dose of atherapeutic latanoprost aqueous composition comprising: about 50 μg oflatanoprost per mL of solution; SAE-CD; pharmaceutically acceptableaqueous liquid carrier; and potassium sorbate of about 0.05 to about0.2% by weight of the unit dose, wherein the solution is suitable forophthalmic administration to a subject in need thereof.
 3. A system fortreating a disease, disorder, condition or symptom of the eye in asubject in need thereof, the system comprising. an aqueous compositioncomprising a therapeutically effective amount of latanoprost, SAE-CD,and a pharmaceutically acceptable aqueous liquid carrier; and anadministration device for ophthalmic administration of the aqueouscomposition to the subject, wherein the composition is provided in thedevice.
 4. The system according to claim 3, wherein the administrationdevice is a dropper, drop-dispensing package, tube, eye spray device, oreye wash unit.
 5. The system according to claim 3, wherein theadministration device comprises plural unit doses of latanoprost.
 6. Amethod of treating, preventing or ameliorating a diseases, disorder,condition, or symptom of the eye that is therapeutically responsive tolatanoprost, the method comprising administering to the eye of a subjectin need thereof a therapeutically effective amount of latanoprost in anaqueous composition comprising: aqueous carrier; SAE-CD; andlatanoprost, wherein the pH of the composition ranges from 5.5 to 7; themolar ratio of SAE-CD to latanoprost ranges from 2:1 to 40:1; theconcentration of latanoprost ranges from 10 to 500 μg/mL; and theconcentration of SAE-CD ranges from 1 to 100 mg/mL.
 7. The method ofclaim 6 comprising: metering into the eye of the subject atherapeutically effective amount of latanoprost that is about 6 μg orless per day, delivered as 1 or more unit doses, wherein each unit doseconsists essentially of a volume of composition of about 25 to 50 μLcomprising about 1 to 2 μg of latanoprost, pharmaceutically acceptableaqueous carrier, SAE-CD, and potassium sorbate present at about 0.05 toabout 0.2% by weight of the unit dose.
 8. The method of claim 6, whereinthe composition comprises: aqueous carrier; SAE-CD; and latanoprost,wherein the pH of the composition ranges from 5.5 to 7; the molar ratioof SAE-CD to latanoprost ranges from 2:1 to 21:1; the concentration oflatanoprost ranges from 25 to 150 μg/mL; and the concentration of SAE-CDranges from 1 to 50 mg/mL.
 9. The invention according to any of claims1-8, wherein the composition is a liquid and at least 98% wt. of thelatanoprost is dissolved in the composition.
 10. The invention accordingto claim 9, wherein the composition further comprises one or moreviscosity modifiers, one or more tonicity modifiers, one or morebuffering agents, one or more preservatives, one or more buffers, one ormore suspending agents, one or more gelling agents, or a combinationthereof.
 11. The invention according to claim 10, wherein the viscosityof the composition is in the range of 1-20,000 cps or is less than 1000cps.
 12. The invention according to any of claims 1-8, wherein: the pHranges from 6 to 7; the molar ratio SAE-CD to latanoprost ranges from4:1 to 21:1; the concentration of latanoprost ranges from 25 to 150μg/mL; and/or the concentration of SAE-CD ranges from 1 to 50 mg/mL. 13.The invention according to claim 12, wherein the composition excludes abenzalkonium chloride.
 14. The invention according to claim 12, whereinthe composition excludes a preservative, and the composition isself-preserved.
 15. The invention according to any of the claims 1-8,wherein the composition is a liquid, syrup, cream or gel.
 16. Theinvention according to any of claims 1-8, wherein a dose of latanoprostcomprises a therapeutically effective amount thereof in a volume ofcomposition of 15 to 150 μL.
 17. The invention according to any of theabove claims, wherein SAE-CD comprises a compound, or mixture ofcompounds, of the Formula 1:

wherein: p is 4, 5 or 6; R₁ is independently selected at each occurrencefrom —OH or —SAET; —SAE is a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, wherein atleast one SAE is independently a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, a—O—(CH₂)_(g)SO₃ ⁻ group, wherein g is 2 to 6, or 2 to 4; and T isindependently selected at each occurrence from the group consisting ofpharmaceutically acceptable cations, provided that at least one R₁ is ahydroxyl moiety and at least one R₁ is —SAET.
 18. The inventionaccording to claim 17, wherein SAE-CD is SBE-α-CD, SBE-β-CD or SBE-γ-CD.19. The invention according to claim 18, wherein average degree ofsubstitution for the SAE-CD ranges from 5 to 7.